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S. Umeda, R. Ayyagari, R. Allikmets, H. Okamoto, M.T. Suzuki, K. Terao, A. Mizota, Y. Yoshikawa, Y. Tanaka, T. Iwata; Linkage and mutation analysis to identify the gene associated with macular degeneration segregating in a cynomolgus monkey (Macaca fascicularis) pedigree. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1825.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To identify the gene associated with early onset autosomal dominant macular degeneration in a large monkey pedigree, which manifests grayish or yellowish white dots in the macula and lipofuscin deposit in the retinal pigment epithelium, using candidate gene approach and linkage analysis. Methods: We cloned the monkey homologues of ABCA4, VMD2, TIMP3, EFEMP1, and ELOVL4 as candidates. Mutation analysis was performed by PCR amplification of exons using DNA from 6 affected and 11 normal monkeys, followed by single strand confirmation polymorphism analysis and direct sequencing. Microsatellite markers linked to human macular degeneration loci were amplified using DNA from 20 affected monkeys and 6 unaffected relatives. Linkage analysis was carried out using MLINK program and affecteds–only model. Results: No pathogenic sequence change was identified in monkey genes homologous to the human VMD2, TIMP3, EFEMP1, and ELOVL4 gene. Sequences of these four monkey genes showed significant homology with their human counterparts. In addition, no significant positive LOD scores were obtained when tested for linkage with STGD1, STGD3, STGD4, ARMD1, DHRD, Sorsby’s fundus dystrophy, VMD2, MCDR1, CORD5, CORD8, and CORD9 loci. Conclusions: Involvement of VMD2, TIMP3, EFEMP1, and ELOVL4 loci has been excluded in the monkey pedigree by linkage, haplotype and mutation analysis. Furthermore, by linkage analysis, we have also excluded the loci for STGD1, STGD4, ARMD1, MCDR1, CORD5, CORD8 and CORD9 conditions showing phenotypic overlap with the disease observed in affected monkeys. Macular degeneration in our monkey pedigree is likely to be due to mutations in a novel gene. Cloning the gene involved in causing macular degeneration in these monkeys will provide a valuable model to study the mechanism of macular degeneration.
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